埼玉医科大学雑誌 第30巻 第3号 (2003年7月) T47-T52頁 ◇論文(図表を含む全文)は，PDFファイルとなっています．
PDF (3.7 MB)
医学博士 甲第857号 平成15年3月28日 （埼玉医科大学）
The Effect of Zinc on Human Thyroid Cancer Cell Line
Akinobu Minagawa (Fourth Department of Internal Medicine, Saitama Medical School, Moroyama, Iruma-gun, Saitama 350-0495, Japan)
Zinc is an essential component of a wide variety of metalloenzymes, transcription factors and other proteins. Intracellular homeostasis of zinc is believed to be critical because of its different biological roles. To attain homeostasis under different conditions, cell must adjust the rate of zinc uptake and efflux, binding to intracellular and extracellular proteins or other molecules, and sequestration into vesicles or organelles. This suggests that proteins involved in controlling such processes would be regulated directly by zinc. The expression of zinc transporters in human thyroid cancer cell line is not unknown.
Zinc has been reported to have potent cytotoxic effect on thyroid cancer cells. Zinc induced necrotic cell death predominantly rather than apoptotic cell death in thyroid cancer cells. In this study, it was demonstrated that the expression of the antiapoptotic proeteins (Bcl-2, Bcl-xL, phosphorylated Bad, and phosphorylated Akt) were increased, whereas the expression of the proapoptotic proteins (Bad and Bax) were decreased following zinc exposure in 8505C thyroid cancer cells. Phosphoinositide 3-kinase (PI3K) inhibitors inhibited the phosphorylation of Akt induced by zinc, suggesting that zinc activates PI3K followed by phosphorylation of Akt and Bad. Phosphorylation of Akt and Bad may prevent the thyroid cancer cells from apoptotic cell death.
The expression of zinc transporter (ZnT)-1 and-4 was demonstrated in 8505C thyroid cancer cells by northern blot anarysis. Because ZnT-1 is a membrane protein that transports zinc out of cells, it is of interest that the expression of ZnT-1 mRNA in 8505C was significantly lower than other human cancer cell lines. In contrast, the expression of ZnT-4 mRNA in 8505C thyroid cancer cell line was markedly increased as compared with other human cancer cell lines. The expression of ZnT-2 and ZnT-3 was not observed even by the polymerase chain reaction (PCR) method. Zinquin, a specific fluorescent probe for zinc, showed an increase in intracytoplasmic zinc concentrations after zinc exposure in 8505C.
In summary, the potent cytotoxic effect of zinc on the thyroid cancer cell line may be due to a decrease in the expression of ZnT-1 that leads to an increase in intracytoplasmic zinc concentration. Although zinc has potent cytotoxic effect, zinc also activates antiapoptotic proteins, especially phosphorylated Akt and Bad, which may prevent the cells from apoptotic cell death.
Keywords: zinc, zinc transportor, thyroid cancer, apoptosis, Akt